Deciphering the interplay between H3K36 and DNA methylation in renal cancer

解读肾癌中 H3K36 和 DNA 甲基化之间的相互作用

基本信息

  • 批准号:
    9896790
  • 负责人:
  • 金额:
    $ 57.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-04-03 至 2023-03-31
  • 项目状态:
    已结题

项目摘要

Clear cell renal carcinoma (ccRCC) is the 8th leading cause of cancer death in the United States. While the majority of localized RCC is cured with surgery, ~30% of patients progress to distant metastases where survival drops to <2 years and for which no curative therapies exist. Over the past five years exciting new findings revealed that genes regulating the epigenome, including SETD2, BAP1, and PBRM1, are mutated in >50% of ccRCC cases. The mechanism by which this class of mutations initiates and drives tumorigenesis, however, remains completely unknown. The epigenome is profoundly disrupted in cancer. One of the best characterized epigenetic marks is DNA methylation (5mC). 5mC is a potent transcriptional repressive signal when present in promoters and enhancers, but paradoxically is associated positively with transcription in gene bodies. During cancer progression, promoters and enhancers of growth regulatory genes are targeted for hypermethylation-mediated silencing while other regions of the genome lose 5mC, such as gene bodies. 5mC mediated by DNA methyltransferases and histone H3 lysine 36 trimethylation (H3K36me3) mediated by SETD2 co-localize in gene bodies, their levels increase with transcription, and DNMT3B binds to H3K36me3 providing a mechanistic link. Our preliminary and published data reveal a novel crosstalk between 5mC and H3K36me3 in ccRCC, in which SETD2 inactivation results in loss of 5mC targeting to gene bodies and dramatic genome-wide DNA hypermethylation, demonstrating that SETD2 mutation represents a new hypermethylator driver gene akin to IDH1/IDH2 mutation. Our long term goal is to use SETD2 as a paradigm for understanding how epigenetic-regulator mutations drive tumorigenesis and how these mutations can be targeted. Our specific hypothesis for this application is that SETD2 mutations drive ccRCC in part by causing global DNA hypermethylation that promotes a more aggressive, metastatic gene expression program. In addition, we hypothesize that this class of ccRCCs is susceptible to DNA hypomethylating agents. We will address this hypothesis with three aims. In aim 1 we will characterize interactions between 5mC/DNMTs and H3K36me3 to define the mechanism by which SETD2 mutation drives aberrant 5mC targeting and gene expression. In aim 2 we interrogate how SETD2 mutation-mediated deregulation of 5mC and transcriptional patterns impact cell growth, metastasis, and susceptibility to epigenome-targeting agents. Finally in aim 3 we define 5mC signatures linked to EMT, and validate and characterize key 5mC deregulation events through which loss of H3K36me3 activity drives a metastatic gene expression program. Our studies will shed new light on how the genome and epigenome interact and yield a detailed picture of how mutation of an epigenetic regulator gene drives tumorigenesis. This is expected to positively affect human health by allowing for a more complete understanding of the molecular etiology underlying cancers with epigenetic regulator mutations and drive discovery of new therapies that specifically target the pathways they deregulate.
肾透明细胞癌(ccRCC)是美国癌症死亡的第8大原因。而 大多数局部RCC通过手术治愈,约30%的患者进展为远处转移, 生存期下降到<2年,并且没有治愈性疗法。在过去的五年里,令人兴奋的新 研究结果显示,调节表观基因组的基因,包括SETD 2,BAP 1和PBRM 1,在 >50%的ccRCC病例。这类突变启动和驱动肿瘤发生的机制, 然而,仍然完全未知。表观基因组在癌症中被严重破坏。一个最好的 表观遗传标记的特征是DNA甲基化(5 mC)。5 mC是一种有效的转录抑制信号 当存在于启动子和增强子中时,但矛盾的是与基因的转录正相关。 尸体在癌症进展过程中,生长调节基因的启动子和增强子被靶向, 高甲基化介导的沉默,而基因组的其他区域失去5 mC,如基因体。5mC 由DNA甲基转移酶介导的组蛋白H3赖氨酸36三甲基化(H3 K36 me 3) SETD 2共定位于基因体中,其水平随着转录而增加,并且DNMT 3B结合H3 K36 me 3 提供机械连接。我们的初步和已发表的数据揭示了5 mC和5 mC之间的新串扰。 - ccRCC中的H3 K36 me 3,其中SETD 2失活导致靶向基因体的5 mC丧失, 戏剧性的全基因组DNA超甲基化,表明SETD 2突变代表了一种新的 类似于IDH 1/IDH 2突变的高甲基化驱动基因。我们的长期目标是使用SETD 2作为 了解表观遗传调节因子突变如何驱动肿瘤发生以及这些突变如何 突变可以被靶向。我们对此应用的具体假设是,SETD 2突变驱动ccRCC 部分原因是导致了整体DNA超甲基化,促进了更具侵略性的转移性基因表达, 程序.此外,我们假设这类ccRCC对DNA低甲基化剂敏感。 我们将以三个目标来讨论这个假设。在目标1中,我们将描述 5 mC/DNMTs和H3 K36 me 3来定义SETD 2突变驱动异常5 mC/DNMTs的机制 靶向和基因表达。在目的2中,我们研究了SETD 2突变介导的5 mC的失调是如何发生的。 和转录模式影响细胞生长、转移和对表观基因组靶向剂的易感性。 最后,在目标3中,我们定义了与EMT相关的5 mC签名,并验证和表征了关键的5 mC放松管制 H3 K36 me 3活性丧失通过这些事件驱动转移性基因表达程序。我们的研究将 揭示了基因组和表观基因组如何相互作用的新的光,并产生了一个详细的图片,如何突变的一个 表观遗传调节基因驱动肿瘤发生。预计这将对人类健康产生积极影响, 为了更全面地了解具有表观遗传调节因子的癌症的分子病因学 突变和驱动新疗法的发现,专门针对他们解除管制的途径。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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Thai Huu Ho其他文献

Quantifying absolute benefit for adjuvant treatment options in renal cell carcinoma: A living interactive systematic review and network meta-analysis
量化肾细胞癌辅助治疗方案的绝对益处:一项生动的交互式系统评价和网络荟萃分析
  • DOI:
    10.1016/j.critrevonc.2022.103706
  • 发表时间:
    2022-07-01
  • 期刊:
  • 影响因子:
    5.600
  • 作者:
    Irbaz Bin Riaz;Qurat Ul Ain Riaz Sipra;Syed Arsalan Ahmed Naqvi;Huan He;Rabbia Siddiqi;Mahnoor Islam;Noureen Asghar;Waleed Ikram;Wenxin Xu;Hongfong Liu;Parminder Singh;Thai Huu Ho;Mehmet Asim Bilen;Yousef Zakharia;Alan Haruo Bryce;Mohammad Hassan Murad
  • 通讯作者:
    Mohammad Hassan Murad

Thai Huu Ho的其他文献

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{{ truncateString('Thai Huu Ho', 18)}}的其他基金

Synthetic Lethal Targeting of SETD2 in Renal Cell Carcinoma
SETD2 在肾细胞癌中的合成致死靶向
  • 批准号:
    10607320
  • 财政年份:
    2023
  • 资助金额:
    $ 57.76万
  • 项目类别:
Deciphering the interplay between H3K36 and DNA methylation in renal cancer
解读肾癌中 H3K36 和 DNA 甲基化之间的相互作用
  • 批准号:
    10363746
  • 财政年份:
    2018
  • 资助金额:
    $ 57.76万
  • 项目类别:
Deciphering the interplay between H3K36 and DNA methylation in renal cancer
解读肾癌中 H3K36 和 DNA 甲基化之间的相互作用
  • 批准号:
    9472131
  • 财政年份:
    2018
  • 资助金额:
    $ 57.76万
  • 项目类别:

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